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. 1990 Dec 25;18(24):7305–7316. doi: 10.1093/nar/18.24.7305

Sequences of human immunoglobulin switch regions: implications for recombination and transcription.

F C Mills 1, J S Brooker 1, R D Camerini-Otero 1
PMCID: PMC332867  PMID: 2124350

Abstract

We have sequenced the entire human S mu and S gamma 4 immunoglobulin heavy chain class switch regions, and have also completed the sequence of human S epsilon. S mu is composed predominantly of GAGCT and GGGCT pentameric repeats, with these units also being found in S epsilon at a much lower density. S mu-S gamma 4 matches are infrequent, but S gamma 4 contains a cluster of repeated sequences similar to units in mouse gamma switch sites and unrelated to the S mu repeats, suggesting that S mu-S gamma homology is not important in mu-gamma switching. We examined our epsilon and gamma 4 sequences for features that could regulate production of 'sterile' transcripts preceding switch recombination. There is an Evolutionarily Conserved Sequence (ECS) upstream from the human and mouse S epsilon regions that overlaps and extends 5' to the start sites for human and mouse epsilon sterile transcripts. Similarly, an ECS upstream from S gamma 4 is homologous to a mouse sequence that overlaps and extends 5' to the start sites for mouse gamma 2b sterile transcripts. The epsilon and gamma 4 conserved segments contain potential Interferon Stimulable Response Elements (ISRE's) that are identical between human epsilon and gamma 4.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ahn B. Y., Dornfeld K. J., Fagrelius T. J., Livingston D. M. Effect of limited homology on gene conversion in a Saccharomyces cerevisiae plasmid recombination system. Mol Cell Biol. 1988 Jun;8(6):2442–2448. doi: 10.1128/mcb.8.6.2442. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Akahori Y., Handa H., Imai K., Abe M., Kameyama K., Hibiya M., Yasui H., Okamura K., Naito M., Matsuoka H. Sigma region located between C mu and C delta genes of human immunoglobulin heavy chain: possible involvement of tRNA-like structure in RNA splicing. Nucleic Acids Res. 1988 Oct 25;16(20):9497–9511. doi: 10.1093/nar/16.20.9497. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Anderson R. A., Kato S., Camerini-Otero R. D. A pattern of partially homologous recombination in mouse L cells. Proc Natl Acad Sci U S A. 1984 Jan;81(1):206–210. doi: 10.1073/pnas.81.1.206. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Benech P., Vigneron M., Peretz D., Revel M., Chebath J. Interferon-responsive regulatory elements in the promoter of the human 2',5'-oligo(A) synthetase gene. Mol Cell Biol. 1987 Dec;7(12):4498–4504. doi: 10.1128/mcb.7.12.4498. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Blackwell T. K., Alt F. W. Mechanism and developmental program of immunoglobulin gene rearrangement in mammals. Annu Rev Genet. 1989;23:605–636. doi: 10.1146/annurev.ge.23.120189.003133. [DOI] [PubMed] [Google Scholar]
  6. Blanar M. A., Baldwin A. S., Jr, Flavell R. A., Sharp P. A. A gamma-interferon-induced factor that binds the interferon response sequence of the MHC class I gene, H-2Kb. EMBO J. 1989 Apr;8(4):1139–1144. doi: 10.1002/j.1460-2075.1989.tb03484.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Boothby M., Gravallese E., Liou H. C., Glimcher L. H. A DNA binding protein regulated by IL-4 and by differentiation in B cells. Science. 1988 Dec 16;242(4885):1559–1562. doi: 10.1126/science.3144043. [DOI] [PubMed] [Google Scholar]
  8. Celada A., Shiga M., Imagawa M., Kop J., Maki R. A. Identification of a nuclear factor that binds to a conserved sequence of the I-A beta gene. J Immunol. 1988 Jun 1;140(11):3995–4002. [PubMed] [Google Scholar]
  9. Dale R. M., McClure B. A., Houchins J. P. A rapid single-stranded cloning strategy for producing a sequential series of overlapping clones for use in DNA sequencing: application to sequencing the corn mitochondrial 18 S rDNA. Plasmid. 1985 Jan;13(1):31–40. doi: 10.1016/0147-619x(85)90053-8. [DOI] [PubMed] [Google Scholar]
  10. Dale T. C., Rosen J. M., Guille M. J., Lewin A. R., Porter A. G., Kerr I. M., Stark G. R. Overlapping sites for constitutive and induced DNA binding factors involved in interferon-stimulated transcription. EMBO J. 1989 Mar;8(3):831–839. doi: 10.1002/j.1460-2075.1989.tb03444.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Decker T., Lew D. J., Cheng Y. S., Levy D. E., Darnell J. E., Jr Interactions of alpha- and gamma-interferon in the transcriptional regulation of the gene encoding a guanylate-binding protein. EMBO J. 1989 Jul;8(7):2009–2014. doi: 10.1002/j.1460-2075.1989.tb03608.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Devereux J., Haeberli P., Smithies O. A comprehensive set of sequence analysis programs for the VAX. Nucleic Acids Res. 1984 Jan 11;12(1 Pt 1):387–395. doi: 10.1093/nar/12.1part1.387. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Ellison J., Buxbaum J., Hood L. Nucleotide sequence of a human immunoglobulin C gamma 4 gene. DNA. 1981;1(1):11–18. doi: 10.1089/dna.1.1981.1.11. [DOI] [PubMed] [Google Scholar]
  14. Esser C., Radbruch A. Rapid induction of transcription of unrearranged S gamma 1 switch regions in activated murine B cells by interleukin 4. EMBO J. 1989 Feb;8(2):483–488. doi: 10.1002/j.1460-2075.1989.tb03401.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Flanagan J. G., Rabbitts T. H. Arrangement of human immunoglobulin heavy chain constant region genes implies evolutionary duplication of a segment containing gamma, epsilon and alpha genes. Nature. 1982 Dec 23;300(5894):709–713. doi: 10.1038/300709a0. [DOI] [PubMed] [Google Scholar]
  16. Ford A. M., Molgaard H. V., Greaves M. F., Gould H. J. Immunoglobulin gene organisation and expression in haemopoietic stem cell leukaemia. EMBO J. 1983;2(6):997–1001. doi: 10.1002/j.1460-2075.1983.tb01533.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Friedman R. L., Stark G. R. alpha-Interferon-induced transcription of HLA and metallothionein genes containing homologous upstream sequences. Nature. 1985 Apr 18;314(6012):637–639. doi: 10.1038/314637a0. [DOI] [PubMed] [Google Scholar]
  18. Gauchat J. F., Lebman D. A., Coffman R. L., Gascan H., de Vries J. E. Structure and expression of germline epsilon transcripts in human B cells induced by interleukin 4 to switch to IgE production. J Exp Med. 1990 Aug 1;172(2):463–473. doi: 10.1084/jem.172.2.463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Gerondakis S. Structure and expression of murine germ-line immunoglobulin epsilon heavy chain transcripts induced by interleukin 4. Proc Natl Acad Sci U S A. 1990 Feb;87(4):1581–1585. doi: 10.1073/pnas.87.4.1581. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Gritzmacher C. A. Molecular aspects of heavy-chain class switching. Crit Rev Immunol. 1989;9(3):173–200. [PubMed] [Google Scholar]
  21. Hennighausen L., Siebenlist U., Danner D., Leder P., Rawlins D., Rosenfeld P., Kelly T., Jr High-affinity binding site for a specific nuclear protein in the human IgM gene. Nature. 1985 Mar 21;314(6008):289–292. doi: 10.1038/314289a0. [DOI] [PubMed] [Google Scholar]
  22. Hisajima H., Nishida Y., Nakai S., Takahashi N., Ueda S., Honjo T. Structure of the human immunoglobulin C epsilon 2 gene, a truncated pseudogene: implications for its evolutionary origin. Proc Natl Acad Sci U S A. 1983 May;80(10):2995–2999. doi: 10.1073/pnas.80.10.2995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Hofker M. H., Walter M. A., Cox D. W. Complete physical map of the human immunoglobulin heavy chain constant region gene complex. Proc Natl Acad Sci U S A. 1989 Jul;86(14):5567–5571. doi: 10.1073/pnas.86.14.5567. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Kageyama R., Pastan I. Molecular cloning and characterization of a human DNA binding factor that represses transcription. Cell. 1989 Dec 1;59(5):815–825. doi: 10.1016/0092-8674(89)90605-3. [DOI] [PubMed] [Google Scholar]
  25. Klar A. J., Strathern J. N., Abraham J. A. Involvement of double-strand chromosomal breaks for mating-type switching in Saccharomyces cerevisiae. Cold Spring Harb Symp Quant Biol. 1984;49:77–88. doi: 10.1101/sqb.1984.049.01.011. [DOI] [PubMed] [Google Scholar]
  26. Lenardo M. J., Staudt L., Robbins P., Kuang A., Mulligan R. C., Baltimore D. Repression of the IgH enhancer in teratocarcinoma cells associated with a novel octamer factor. Science. 1989 Jan 27;243(4890):544–546. doi: 10.1126/science.2536195. [DOI] [PubMed] [Google Scholar]
  27. Levy D. E., Kessler D. S., Pine R., Reich N., Darnell J. E., Jr Interferon-induced nuclear factors that bind a shared promoter element correlate with positive and negative transcriptional control. Genes Dev. 1988 Apr;2(4):383–393. doi: 10.1101/gad.2.4.383. [DOI] [PubMed] [Google Scholar]
  28. Lutzker S., Alt F. W. Structure and expression of germ line immunoglobulin gamma 2b transcripts. Mol Cell Biol. 1988 Apr;8(4):1849–1852. doi: 10.1128/mcb.8.4.1849. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Lutzker S., Rothman P., Pollock R., Coffman R., Alt F. W. Mitogen- and IL-4-regulated expression of germ-line Ig gamma 2b transcripts: evidence for directed heavy chain class switching. Cell. 1988 Apr 22;53(2):177–184. doi: 10.1016/0092-8674(88)90379-0. [DOI] [PubMed] [Google Scholar]
  30. Marcu K. B., Lang R. B., Stanton L. W., Harris L. J. A model for the molecular requirements of immunoglobulin heavy chain class switching. Nature. 1982 Jul 1;298(5869):87–89. doi: 10.1038/298087a0. [DOI] [PubMed] [Google Scholar]
  31. Max E. E., Battey J., Ney R., Kirsch I. R., Leder P. Duplication and deletion in the human immunoglobulin epsilon genes. Cell. 1982 Jun;29(2):691–699. doi: 10.1016/0092-8674(82)90185-4. [DOI] [PubMed] [Google Scholar]
  32. Mills F. C., Fisher L. M., Kuroda R., Ford A. M., Gould H. J. DNase I hypersensitive sites in the chromatin of human mu immunoglobulin heavy-chain genes. Nature. 1983 Dec 22;306(5945):809–812. doi: 10.1038/306809a0. [DOI] [PubMed] [Google Scholar]
  33. Mitchell P. J., Tjian R. Transcriptional regulation in mammalian cells by sequence-specific DNA binding proteins. Science. 1989 Jul 28;245(4916):371–378. doi: 10.1126/science.2667136. [DOI] [PubMed] [Google Scholar]
  34. Mowatt M. R., Dunnick W. A. DNA sequence of the murine gamma 1 switch segment reveals novel structural elements. J Immunol. 1986 Apr 1;136(7):2674–2683. [PubMed] [Google Scholar]
  35. Nikaido T., Nakai S., Honjo T. Switch region of immunoglobulin Cmu gene is composed of simple tandem repetitive sequences. Nature. 1981 Aug 27;292(5826):845–848. doi: 10.1038/292845a0. [DOI] [PubMed] [Google Scholar]
  36. Nikaido T., Yamawaki-Kataoka Y., Honjo T. Nucleotide sequences of switch regions of immunoglobulin C epsilon and C gamma genes and their comparison. J Biol Chem. 1982 Jul 10;257(13):7322–7329. [PubMed] [Google Scholar]
  37. Pont G., Degroote F., Picard G. Illegitimate recombination in the histone multigenic family generates circular DNAs in Drosophila embryos. Nucleic Acids Res. 1988 Sep 26;16(18):8817–8833. doi: 10.1093/nar/16.18.8817. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Pustell J., Kafatos F. C. A convenient and adaptable package of computer programs for DNA and protein sequence management, analysis and homology determination. Nucleic Acids Res. 1984 Jan 11;12(1 Pt 2):643–655. doi: 10.1093/nar/12.1part2.643. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Radcliffe G., Lin Y. C., Julius M., Marcu K. B., Stavnezer J. Structure of germ line immunoglobulin alpha heavy-chain RNA and its location on polysomes. Mol Cell Biol. 1990 Jan;10(1):382–386. doi: 10.1128/mcb.10.1.382. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Ravetch J. V., Kirsch I. R., Leder P. Evolutionary approach to the question of immunoglobulin heavy chain switching: evidence from cloned human and mouse genes. Proc Natl Acad Sci U S A. 1980 Nov;77(11):6734–6738. doi: 10.1073/pnas.77.11.6734. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Reid L. E., Brasnett A. H., Gilbert C. S., Porter A. C., Gewert D. R., Stark G. R., Kerr I. M. A single DNA response element can confer inducibility by both alpha- and gamma-interferons. Proc Natl Acad Sci U S A. 1989 Feb;86(3):840–844. doi: 10.1073/pnas.86.3.840. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Rothman P., Chen Y. Y., Lutzker S., Li S. C., Stewart V., Coffman R., Alt F. W. Structure and expression of germ line immunoglobulin heavy-chain epsilon transcripts: interleukin-4 plus lipopolysaccharide-directed switching to C epsilon. Mol Cell Biol. 1990 Apr;10(4):1672–1679. doi: 10.1128/mcb.10.4.1672. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Sideras P., Mizuta T. R., Kanamori H., Suzuki N., Okamoto M., Kuze K., Ohno H., Doi S., Fukuhara S., Hassan M. S. Production of sterile transcripts of C gamma genes in an IgM-producing human neoplastic B cell line that switches to IgG-producing cells. Int Immunol. 1989;1(6):631–642. doi: 10.1093/intimm/1.6.631. [DOI] [PubMed] [Google Scholar]
  44. Snapper C. M., Paul W. E. Interferon-gamma and B cell stimulatory factor-1 reciprocally regulate Ig isotype production. Science. 1987 May 22;236(4804):944–947. doi: 10.1126/science.3107127. [DOI] [PubMed] [Google Scholar]
  45. Sobel E., Martinez H. M. A multiple sequence alignment program. Nucleic Acids Res. 1986 Jan 10;14(1):363–374. doi: 10.1093/nar/14.1.363. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Stavnezer-Nordgren J., Sirlin S. Specificity of immunoglobulin heavy chain switch correlates with activity of germline heavy chain genes prior to switching. EMBO J. 1986 Jan;5(1):95–102. doi: 10.1002/j.1460-2075.1986.tb04182.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Stavnezer J., Radcliffe G., Lin Y. C., Nietupski J., Berggren L., Sitia R., Severinson E. Immunoglobulin heavy-chain switching may be directed by prior induction of transcripts from constant-region genes. Proc Natl Acad Sci U S A. 1988 Oct;85(20):7704–7708. doi: 10.1073/pnas.85.20.7704. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Thyphronitis G., Tsokos G. C., June C. H., Levine A. D., Finkelman F. D. IgE secretion by Epstein-Barr virus-infected purified human B lymphocytes is stimulated by interleukin 4 and suppressed by interferon gamma. Proc Natl Acad Sci U S A. 1989 Jul;86(14):5580–5584. doi: 10.1073/pnas.86.14.5580. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Ueda S., Nakai S., Nishida Y., Hisajima H., Honjo T. Long terminal repeat-like elements flank a human immunoglobulin epsilon pseudogene that lacks introns. EMBO J. 1982;1(12):1539–1544. doi: 10.1002/j.1460-2075.1982.tb01352.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Voelkel-Meiman K., Keil R. L., Roeder G. S. Recombination-stimulating sequences in yeast ribosomal DNA correspond to sequences regulating transcription by RNA polymerase I. Cell. 1987 Mar 27;48(6):1071–1079. doi: 10.1016/0092-8674(87)90714-8. [DOI] [PubMed] [Google Scholar]
  51. Watt V. M., Ingles C. J., Urdea M. S., Rutter W. J. Homology requirements for recombination in Escherichia coli. Proc Natl Acad Sci U S A. 1985 Jul;82(14):4768–4772. doi: 10.1073/pnas.82.14.4768. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. White M. B., Word C. J., Humphries C. G., Blattner F. R., Tucker P. W. Immunoglobulin D switching can occur through homologous recombination in human B cells. Mol Cell Biol. 1990 Jul;10(7):3690–3699. doi: 10.1128/mcb.10.7.3690. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Word C. J., White M. B., Kuziel W. A., Shen A. L., Blattner F. R., Tucker P. W. The human immunoglobulin C mu-C delta locus: complete nucleotide sequence and structural analysis. Int Immunol. 1989;1(3):296–309. doi: 10.1093/intimm/1.3.296. [DOI] [PubMed] [Google Scholar]

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